Barth syndrome:: TAZ gene mutations, mRNAs, and evolution
Barth syndrome:: TAZ gene mutations, mRNAs, and evolution
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DOI：
10.1002/ajmg.a.30661
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发表时间：
2005-05-01
影响因子：
2
通讯作者：
Gonzalez, IL
中科院分区：
文献类型：
--
作者：
Gonzalez, IL
Barth综合征（MIM 302060）是一种x连锁疾病，包括扩张性心肌病、中性粒细胞减少症、发育不良、线粒体异常和3-甲基戊二酸尿。突变基因TAZ于1996年首次被描述，它似乎产生了大量的选择性剪接mrna，其转录起始位于外显子I和3的上游。从那时起，在所有外显子中都发现了致病突变，包括最近在有争议的外显子5中发现的错义突变。由于最初描述的内含子2的第二次转录起始，以及外显子3的框内翻译起始，我们假设外显子1和2突变的受试者会产生更正常的“短产物”，这可能会减弱其表型。此外，确定哪些剪接变体具有潜在的功能是很有意义的，因为酵母和啮齿动物中不存在外显子5，而缺乏该外显子的变体数量最多。利用RT-PCR技术，我们鉴定了9名Barth综合征患者和2名健康对照者培养淋巴细胞中的TAZ mrna。灵长类动物的TAZ基因和mrna也被包括在内。研究发现：(1)转录起始位点只有一个，正常的选择性剪接组合仅限于全长、Delta 5、Delta 7、Delta 5和Delta 7；(2)内含子I和2中有两个可选的剪接位点可能产生框内产物；(3)外显子5在灵长类谱系中进化为“外显子”，发生在旧大陆猴与类人猿灵长类分离之后；(4)我们的结果表明淋巴细胞中只存在两种功能性蛋白变体：A5和全长。虽然外显子5在酵母和猴子中似乎不是TAZ功能所必需的，但在类人猿灵长类动物中它进化为高度保守的剪接外显子，以及最近在Barth综合征患者中发现的外显子5突变表明全长变异对TAZ功能很重要。(c) 2005 Wiley-Liss, Inc。
Barth syndrome (MIM 302060) is an X-linked condition that includes dilated cardiomyopathy, neutropenia, failure to thrive, abnormal mitochondria, and 3-methylglutaconic aciduria. The mutated gene, TAZ, first described in 1996, appeared to produce a large set of alternatively spliced mRNAs with initiations of transcription upstream of exons I and 3. Since then, disease-causing mutations have been found in all exons including, most recently, a missense mutation in the controversial exon 5. Because of the initially described second initiation of transcription in intron 2, with in-frame initiation of translation in exon 3, we hypothesized that subjects with mutations in exons 1 and 2 would produce more normal "short product" that might attenuate their phenotype. Moreover, it was of interest to determine which splice variants were potentially functional as exon 5 is not present in yeast and rodents, and the variant lacking this exon is the most abundant. Using RT-PCR, we characterized TAZ mRNAs in cultured lymphocytes from nine subjects with Barth syndrome and two healthy controls. The TAZ genes and mRNAs of primates were also included. We found the following: (1) there is only one site for initiation of transcription, and the normal alternatively spliced assortment is limited to full-length, Delta 5, Delta 7, Delta 5 Delta 7; (2) there are two alternative splice sites within introns I and 2 that could potentially produce an in-frame product; (3) exon 5 evolved into "exonhood" in the primate lineage after the split between Old World monkeys and hominoid primates; and (4) our results suggest that only two functional protein variants exist in lymphocytes: A5 and full-length. Although exon 5 does not appear to be required for TAZ function in yeast and monkeys, its evolution to a highly conserved spliced exon in hominoid primates and the recent finding of an exon 5 mutation in a patient with Barth syndrome suggest that the full-length variant is important to TAZ function. (c) 2005 Wiley-Liss, Inc.